Among the barriers to successful cancer therapy is the development of drug resistance by tumors. Drug resistance can be mediated by many mechanisms. Of the cell-based mechanisms, ATP-driven xenobiotic efflux of drugs is mediated by P-glycoprotein (also referred to herein as “P-gp”), the product of the mdr1 gene. P-gp is found on a variety of normal tissues, including endothelium and biliary duct cells. P-gp is a member of a large family of ATP-binding cassette proteins, many of which are responsible for removal of toxic substances to the extracellular space.
P-gp recognizes and removes molecules which share characteristics including hydrophobic structures and large ring systems. Many drugs used in the treatment of cancer are P-gp substrates. Thus, one mechanism of cell-based resistance is drug export by P-gp. Such resistance can be conferred by mutation of P-gp to increase the affinity of P-gp for the drug molecule, by increasing the rate of transporter function, and/or by increasing the number of P-gp transporters per cell. The latter mechanism is most often mediated by gene amplification. To overcome P-gp mediated resistance, inhibitors of P-gp can be used. However, the efficacy of such inhibitors can be limited due to mutation of the P-gp transporter and/or gene amplification resulting in increased wild-type or mutant P-gp transporters at the cell surface. Administration of P-gp inhibitors also can be associated with toxicity in patients.
Therefore, the development of drugs that can circumvent P-gp-mediated drug resistance could have significant clinical benefit.